A 50 year old lady is given methotrexate for severe rheumatoid disease causing joint pains and functional limitation. She also has to be given folinic rescue therapy. Which of the following is the mechanism by which methotrexate acts?
**Core Concept**
Methotrexate is an antimetabolite and antifolate drug used in the treatment of rheumatoid arthritis. It acts by inhibiting dihydrofolate reductase (DHFR), an enzyme crucial for the synthesis of tetrahydrofolate (THF) from dihydrofolate (DHF). THF is essential for DNA synthesis and repair.
**Why the Correct Answer is Right**
Methotrexate competes with folate for the active site of DHFR, thereby inhibiting the enzyme's activity. This inhibition leads to a decrease in the levels of THF, which is necessary for the synthesis of purines and pyrimidines. As a result, DNA synthesis and cell replication are impaired, particularly in rapidly dividing cells such as those found in rheumatoid synovium. This mechanism is responsible for the anti-inflammatory and immunosuppressive effects of methotrexate in the treatment of rheumatoid arthritis.
**Why Each Wrong Option is Incorrect**
* **Option A:** Incorrect because methotrexate does not act by inhibiting cyclooxygenase (COX) enzymes, which are involved in the synthesis of prostaglandins and are targeted by nonsteroidal anti-inflammatory drugs (NSAIDs).
* **Option B:** Incorrect because methotrexate does not act by inhibiting the renin-angiotensin-aldosterone system (RAAS), which is involved in blood pressure regulation and electrolyte balance.
* **Option C:** Incorrect because methotrexate does not act by stimulating the release of cytokines, which are involved in the inflammatory response and are typically pro-inflammatory.
**Clinical Pearl / High-Yield Fact**
Folinic acid rescue therapy is used to mitigate the side effects of methotrexate by providing a bypass for the DHFR inhibition. This allows for the continued synthesis of THF and helps to restore normal cellular function.
**Correct Answer:** C. Inhibition of dihydrofolate reductase (DHFR).